Drug resistance remains a major obstacle to the successful treatment of many cancers. The development of multidrug-resistance (MDR) due to the overexpression of P-glycoprotein (P-gp) is one major mechanism of resistance. During our previous grant period, we demonstrated the P-gp can be found in various drug-resistant tumors including breast cancer, multiple myeloma, malignant lymphoma, and myelogenous leukemia. In vitro, MDR could be blocked by several non-cytotoxic drugs including verapamil. When tested clinically, a subset of patients with multiple myeloma and malignant lymphoma benefitted from the addition of verapamil to chemotherapy; however, patients ultimately became resistant to be effects of verapamil and their disease progressed rapidly. Large doses of verapamil were also required which resulted in significant systemic toxicity. For these reasons, verapamil is not an ideal efficacious means of preventing or circumventing P-gp-mediated resistance. The primary objective of this project is to investigate mechanisms of drug resistance and develop means of prevention or circumvention. A preclinical model that includes in vitro and in vivo analysis has been developed to evaluate potential new drugs (chemosensitizers) that can block P-gp- mediated drug resistance. Those agents which appear most promising in this pre-clinical model will then be evaluated in the clinic. Therapeutic outcome in these clinical trials will be correlated with P- gp/mdr1 expression and pharmacokinetics of cytotoxic agents and chemosensitizers. Discovery of new agents to reverse MDR may result in improved therapeutic outcome for certain cancers.